p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signaling pathways (p38/JNK pathway)

The p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways are two major branches of the mitogen-activated protein kinase cascade that respond primarily to environmental stress and pro-inflammatory cytokines (Kyriakis & Avruch, 2012). These pathways are characterized by a three-tier kinase architecture where MAP3Ks activate MAP2Ks, which then dually phosphorylate the TXY motif in the activation loop of p38 and JNK (Zhang & Liu, 2002). Once activated, these kinases regulate a wide array of cellular processes, including the stress response, apoptosis, cell cycle arrest, and the production of inflammatory mediators like TNF-alpha and IL-6. In pathological states, chronic activation of p38 and JNK is associated with the progression of inflammatory diseases such as rheumatoid arthritis, as well as neurodegenerative conditions and various malignancies (Hammaker & Firestein, 2010). Consequently, they have been targeted by numerous small-molecule inhibitors designed to block their catalytic activity, although clinical development has often been hampered by systemic toxicities and compensatory signaling mechanisms (Bubici & Papa, 2014). These inhibitors typically function through ATP-competitive mechanisms, and their efficacy is often monitored via the phosphorylation status of downstream substrates like c-Jun or the reduction of circulating inflammatory biomarkers.

Other names

Stress-activated protein kinase pathwaySAPK pathwayMAPK signaling cascadec-Jun N-terminal kinase pathwayp38 mitogen-activated protein kinase pathway

Small-molecule inhibition of the catalytic activity of p38 or JNK kinases, primarily through ATP-competitive or allosteric binding, to prevent the phosphorylation of downstream transcription factors and the subsequent expression of pro-inflammatory genes.